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Site-selective photoinduced cleavage and profiling of DNA by chiral semiconductor nanoparticles

Abstract

Gene editing is an important genetic engineering technique that enables gene manipulation at the molecular level. It mainly relies on engineered nucleases of biological origin, whose precise functions cannot be replicated in any currently known abiotic artificial material. Here, we show that chiral cysteine-modified CdTe nanoparticles can specifically recognize and, following photonic excitation, cut at the restriction site GAT′ATC (′ indicates the cut site) in double-stranded DNA exceeding 90 base pairs, mimicking a restriction endonuclease. Although photoinduced reactive oxygen species are found to be responsible for the cleavage activity, the sequence selectivity arises from the affinity between cysteine and the conformation of the specific DNA sequence, as confirmed by quantum-chemical calculations. In addition, we demonstrate non-enzymatic sequence-specific DNA incision in living cells and in vivo using these CdTe nanoparticles, which may help in the design of abiotic materials for gene editing and other biological applications.

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Fig. 1: Strategy for site-selective DNA cleavage.
Fig. 2: Chiral CdTe nanoparticle preparation and characterization.
Fig. 3: Site-selective DNA cleavage.
Fig. 4: Specific binding and conformational change between target DNA and chiral nanoparticles.
Fig. 5: Mechanism of DNA cleavage.
Fig. 6: Photoinduced DNA cleavage in living cells and in vivo.

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Acknowledgements

This work was supported financially by the National Natural Science Foundation of China (21522102, 21631005, 21771090, 21673104 and 21471068). We also thank the Brazilian funding agencies Financiadora de Estudos e Projetos (FINEP) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grants 2012/15147-4 and 2013/07296-2) for financial support. The authors acknowledge the National Laboratory for Scientific Computing (LNCC/MCTI, Brazil) and UFSCar for providing the high-performance computing resources of the SDumont supercomputer (http://sdumont.lncc.br) and of the Could@UFSCar, respectively, both of which have contributed to the results reported in this paper. A.F.d.M. thanks Ministério da Educação/Programa de Educação Tutorial for a fellowship.

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H.K., N.A.K. and C.X. conceived the project and designed the experiments. M.S. was responsible for DNA cutting and spectroscopic measurements. L.X. and A.Q. carried out cell and ITC experiments. T.H. and A.Q. were responsible for chiral CdTe nanoparticles synthesis and DNA electrophoresis. W.M. and C.H. carried out synchrotron small-angle X-ray scattering, X-ray photoelectron spectroscopy and transient absorption spectrum experiments. F.M.C and A.F.M. developed the models for free energy calculation. P.Z. and X.W. developed the DFT model. H.K. and M.S. carried out the studies in vivo. H.K. conceptualized the work. C.X. supervised the study and N.A.K. provided advice regarding the idea. H.K. and C.X. analysed the results and wrote the manuscript. H.K., C.X. and N.A.K. discussed the results and commented on the manuscript.

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Correspondence to Hua Kuang.

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Supplementary characterization and calculation details, Supplementary Figures 1–156, Supplementary Tables 1–17

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Sun, M., Xu, L., Qu, A. et al. Site-selective photoinduced cleavage and profiling of DNA by chiral semiconductor nanoparticles. Nature Chem 10, 821–830 (2018). https://doi.org/10.1038/s41557-018-0083-y

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